WO1996039393A1 - Procede de preparation d'urees cycliques n,n'-disubstituees - Google Patents

Procede de preparation d'urees cycliques n,n'-disubstituees Download PDF

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Publication number
WO1996039393A1
WO1996039393A1 PCT/US1996/008556 US9608556W WO9639393A1 WO 1996039393 A1 WO1996039393 A1 WO 1996039393A1 US 9608556 W US9608556 W US 9608556W WO 9639393 A1 WO9639393 A1 WO 9639393A1
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Prior art keywords
substituted
alkyl
phenyl
och
heterocyclic ring
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PCT/US1996/008556
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English (en)
Inventor
Thomas Edgar Smyser
Pasquale Nicholas Confalone
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The Du Pont Merck Pharmaceutical Company
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Priority to EP96917066A priority Critical patent/EP0830349B1/fr
Priority to AT96917066T priority patent/ATE190974T1/de
Priority to AU59752/96A priority patent/AU700805B2/en
Priority to DK96917066T priority patent/DK0830349T3/da
Priority to DE69607344T priority patent/DE69607344T2/de
Priority to MX9709125A priority patent/MX9709125A/es
Priority to NZ309557A priority patent/NZ309557A/en
Priority to JP9501114A priority patent/JPH11506765A/ja
Publication of WO1996039393A1 publication Critical patent/WO1996039393A1/fr
Priority to GR20000400893T priority patent/GR3033199T3/el

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates generally to methods for the preparation of N,N'-disubstituted cyclic ureas from linear diaminodiols. These cyclic urea compounds are useful as HIV protease inhibitor compounds for the treatment of HIV infection.
  • the starting materials for the methods of the present invention are linear diamino diols. These compounds include nonpeptide C-2 symmetric and
  • HIV human immunodeficiency virus
  • N,N'-disubstituted cyclic urea products of the methods of the present invention have also exhibited biological activity as human
  • HIV immunodeficiency virus
  • Acetonide has been used to protect the diol function in the preparation of linear HIV protease inhibitors (Baker et al., J. Org. Chem. 58, 3277-3284 (1993); Baker et al., Tetrahedron Lett . 33, 1581-1584 (1992)).
  • cyclic carbonyl compounds and derivatives thereof which are useful as HIV protease inhibitors for the treatment of HIV infection.
  • Such cyclic compounds which may be made using the processes of the present invention, are non-peptidic, low molecular weight, orally bioavailable compounds useful as inhibitors of HIV protease and for the treatment of HIV infection.
  • Serial Number 08/269,320 discloses a process for the preparation of nitrogen-unsubstituted dihydroxy cyclic ureas having an acetonide protecting group for the diol as shown below in Scheme 2.
  • the cyclization to the cyclic urea takes place on the diamino diol (VI) in which nitrogen is unprotected and the hydroxyls bear an acyclic protecting group.
  • the diol protecting group had to be changed midway through the synthesis in order to optimize the cyclization and alkylation yields.
  • the present invention provides improved processes for the synthesis of such cyclic urea HIV protease inhibitor compounds and processes for the synthesis of
  • the present invention comprises a process which allows the entire synthetic sequence leading to the desired HIV protease inhibitors to be carried out using the inexpensive acetonide or oxydimethylene-1,3-diyl protecting groups.
  • the present invention comprises an initial reductive alkylation of the diamine affording a crystalline intermediate in high yield.
  • phosgene in high yield to produce another crystalline intermediate, providing an optimal process.
  • Advantages of the present invention include: a) reduction in the number of chemical steps; b) increase in overall yield; and c) formation of crystalline intermediates.
  • the present invention comprises processes for the preparation of nitrogen substituted cyclic urea
  • R 4 and R 7 are independently selected from the following groups:
  • R 11 is selected from one or more of the following:
  • C 1 -C 4 alkyl substituted with -NR 13 R 14 C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, pyridylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino,
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11A is selected from one or more of the following:
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0-3 R12A.
  • heterocyclic ring system said carbocyclic or heterocyclic ring system being optionally substituted with Cl, F, Br, CN, NO 2 , CF 3 , C 1 -
  • R 12 when a substituent on carbon, is selected from one or more of the following:
  • halogen hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 7 - C 10 arylalkyl, C 1 -C 4 alkoxy, -CO 2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, -OR 13 , -NR 13 R 14 , C 1 - C 4 alkyl substituted with -NR 13 R 14 , C 2 -C 6 alkoxyalkyl optionally substituted with
  • R 12 when a substituent on nitrogen, is selected from one or more of the following:
  • R 12A when a substituent on carbon, is selected from one or more of the following:
  • halogen hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 7 - C 10 arylalkyl, C 1 -C 4 alkoxy, -CO 2 H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, -OR 13A , C 2 -C 6 alkoxyalkyl optionally substituted with
  • R 12A may be a 3- or 4- carbon chain attached to
  • R 12A when a substituent on nitrogen, is selected from one or more of the following:
  • R 13 is independently selected from:
  • R 14 is independently selected from: hydrogen, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, phenyl, benzyl, an amine protecting group when R 14 is bonded to N, a hydroxyl or carboxyl protecting group when R 14 is bonded to 0; and
  • R 13 and R 14 can alternatively join to form -(CH 2 ) 4 -,
  • R 13A and R 14A are independently selected from: H, C 1 -C 6 alkyl
  • R 13A and R 14A can alternatively join to form -(CH 2 ) 4 -,
  • R 15 is H or CH 3 ;
  • R 16 is independently selected from:
  • haloalkoxy C 1 -C 4 alkoxy, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenethyl, phenoxy, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 7 - C 10 arylalkyl, C 2 -C 6 alkoxyalkyl, C 1 -C 4
  • alkylcarbonyloxy C 1 -C 4 alkylcarbonyl
  • benzyloxy, C 3 -C 6 cycloalkoxy, or phenyl said phenyl being optionally substituted with Cl, F, Br, CN, NO 2 , CF 3 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy or OH, or
  • heterocyclic ring system said carbocyclic or heterocyclic ring system being optionally substituted with Cl, F, Br, CN, NO 2 , CF 3 , C 1 - C 4 alkyl, C 1 -C 4 alkoxy or OH;
  • R 20 and R 21 are independently selected from:
  • R 20 and R 21 may also be taken together along with the oxygen atoms to which they are attached to form a group selected from the group consisting of:
  • n 0, 1 or 2;
  • R 22 is selected from the following:
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 23 R 22 ;
  • R 31 is selected from one or more of the following:
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 32 when a substituent on carbon, is selected from one or more of the following:
  • p 0, 1, or 2
  • n 1 or 2;
  • R 32 when a substituent on nitrogen, is selected from one or more of the following:
  • R 40 is selected from: H, C 1 -C 3 alkyl
  • R 41 is selected from:
  • R 4 , R 7 , R 22 and R 23 including but not limited to, amines, carboxyls, ketones, aldehydes, hydrazines, guanidines,
  • hydroxaminc acids, alcohols, oximes, and thiols that are reactive in steps (l) and (2) of the present process are protected such that the
  • step (2) cyclic urea formation: contacting the secondary amine of formula (II) in a suitable aprotic solvent at a suitable temperature in the presence of at least about one molar equivalent of a hindered amine base with at least about 0.3 molar equivalents of a suitable cyclizing agent at a suitable rate and for a period of time sufficient to form a compound of formula (III):
  • R 4 and R 7 are independently selected from the following groups:
  • R 11 is selected from one or more of the following:
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11A is selected from one or more of the following:
  • R 12 when a substituent on carbon, is selected from one or more of the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur.
  • R 12 when a substituent on nitrogen, is selected from one or more of the following:
  • R 12A when a substituent on carbon, is selected from one or more of the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur.
  • R 12A when a substituent on nitrogen, is selected from one or more of the following:
  • cycloalkylmethyl C 2 -C 6 alkoxyalkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, CF 3 , 2-(1-morpholino) ethoxy, -CO 2 H, hydroxamic acid, hydrazide,
  • a heterocycle selected from the group consisting of :
  • R 14 is independently selected from:
  • R 13 and R 14 can alternatively join to form -(CH 2 ) 4 -,
  • R 13A and R 14A are independently selected from: H, C 1 -C 6 alkyl
  • R 13A and R 14A can alternatively join to form -(CH 2 ) 4 -,
  • R 15 is H or CH 3 ;
  • R 16 is independently selected from:
  • phenyl being optionally substituted with Cl, F, Br, CN, NO 2 , CF 3 , OCH 3 or OH;
  • R 20 and R 21 are independently selected from:
  • R 20 and R 21 may also be taken together along with the oxygen atoms to which they are attached to form a group selected from the group consisting of:
  • R 22 is selected from the following:
  • R23 R 22 .
  • R 31 is selected from one or more of the following:
  • heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 32 when a substituent on carbon, is selected from one or more of the following:
  • cycloalkylmethyl C 7 -C 10 arylalkyl, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 alkylcarbonyloxy, -NHSO 2 R 14 , benzyloxy, halogen, 2-(1-morpholino) ethoxy, -CO 2 R 13 , -CONR 13 NR 13 R 14 , cyano, sulfonamide, -CHO, C 3 - C 6 cycloalkoxy, -NR 13 R 14 , -NO 2 , -OR 13 ,
  • R 32 when a substituent on nitrogen, is selected from one or more of the following:
  • R 40 is selected from: H, C 1 -C 3 alkyl
  • R 41 is selected from:
  • R 4 and R 7 are independently selected from the following groups:
  • R 11 is selected from one or more of the following:
  • R 12 aryl substituted with 0-2 R 12 ; a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl,
  • R 11A is selected from one or more of the following:
  • R 12A aryl (C 1 -C 3 alkyl)- substituted with 0-2 R 12A , aryl substituted with 0-2 R 12A ; or NO 2 , cyano, C 1 -C 6 alkyl, or phenyl, said phenyl
  • heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 R 12A ; R 12 , when a substituent on carbon, is selected from one or more of the following:
  • cycloalkyl C 3 -C 6 cycloalkylmethyl, C 7 -C 10 arylalkyl, C 2 .-C 4 alkoxy, formyl, C 3 -C 6
  • R 12 when a substituent on nitrogen, is methyl
  • R 12A when a substituent on carbon, is selected from one or more of the following:
  • cycloalkyl C 3 -C 6 cycloalkylmethyl, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, formyl, C 3 -C 6
  • R 12A when a substituent on nitrogen, is selected from one or more of the following:
  • R 13 is independently selected from the group consisting of:
  • R 13 is bonded to O
  • R 14 is independently selected from the group consisting of:
  • R 13 and R 14 can alternatively join to form -(CH 2 ) 4 -,
  • R 13A and R 14A are independently selected from: H, C 1 -C 6 alkyl
  • R 13A and R 14A can alternatively join to form -(CH 2 ) 4 -,
  • R 15 is H or CH 3 ;
  • R 16 is independently selected from:
  • phenyl being optionally substituted with Cl, F, Br, CN, NO 2 , CF 3 , OCH 3 or OH;
  • R 22 is selected from the following:
  • heterocycle selected from the group consisting of thiazole, indazole, thieno [2,3-c] pyrazole and thieno [3,2-c] pyrazole, said heterocycle substituted with 0-2 R 31 ;
  • R 23 R 22 ;
  • R 31 is selected from one or more of the following:
  • R 32 when a substituent on carbon, is selected from one or more of the following:
  • R 32 when a substituent on nitrogen, is selected from one or more of the following:
  • R 4 and R 7 are independently C 1 -C 3 alkyl substituted with 0-1 R 11 ;
  • R 11 is selected from one or more of the following:
  • R11 A is selected from one or more of the following:
  • R 12A aryl substituted with 0-2 R 12A ;
  • heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 R 12A ;
  • R 12 when a substituent on carbon, is selected from one or more of the following:
  • cycloalkyl C 3 -C 6 cycloalkylmethyl, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, formyl, C 3 -C 6
  • R 12 when a substituent on nitrogen, is methyl
  • R 12A when a substituent on carbon, is selected from one or more of the following:
  • cycloalkyl C 3 -C 6 cycloalkylmethyl, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, formyl, C 3 -C 6 cycloalkoxy, -OR 13A , C 2 -C 6 alkoxyalkyl
  • R 12A when a substituent on nitrogen, is methyl
  • R 13 is independently selected from the group consisting of:
  • R 13 and R 14 can alternatively join to form -(CH 2 ) 4 -,
  • R 13A and R 14A are independently selected from: H, C 1 -C 6 alkyl
  • R 13A and R 14A can alternatively join to form -(CH 2 ) 4 -,
  • R 15 is H or CH 3 ;
  • R 22 is selected from the following:
  • heterocycle selected from the group consisting of thiazole, indazole, thieno [2,3-c] pyrazole and thieno [3,2-c] pyrazole, said heterocycle substituted with 0-2 R 31 ;
  • R 23 R 22 ;
  • R 31 is selected from one or more of the following:
  • R 32 when a substituent on carbon, is selected from one or more of the following:
  • R 32 when a substituent on nitrogen, is methyl.
  • R 4 and R 7 are independently selected from:
  • R 22 is selected from the group consisting of:
  • cyclopropylmethyl, n-butyl, i-butyl, CH 2 CH C(CH 3 ) 2 , pyridinylmethyl, pyridinyl, methallyl, n-pentyl, i- pentyl, hexyl, phenyl, isoprenyl, propargyl, picolinyl, methoxymethyl, cyclohexyl, dimethyl- butyl, ethoxymethyl, methyloxazolinylmethyl, naphthyl, methyloxazolinyl, vinyloxymethyl, pentafluorophenyl, quinolinyl, carboxyphenyl, chloro-thienyl, benzyloxyphenyl, biphenyl,
  • adamantyl cyelopropylmethoxyphenyl, methoxyphenyl, methylphenyl, ethoxyphenyl, hydroxyphenyl,
  • tetrazolylphenyl dimethylallyl, aminomethylphenyl, (O-benzyl-formaldoxime) phenyl, (O-methyl- formaldoxime) phenyl, (CH 3 O 2 CO)-phenyl,
  • N,N-dimethylaminoearbonylphenyl (HOCH 2 CH(OH)CH 2 O)- phenyl, hydroxyethoxyphenyl (oxazolidinyl)-phenyl, (hydroxyl) pentyl, pentenyl, (hydroxy) heptyl,
  • protease inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases as demonstrated by their HIV
  • the compounds of formula (IV) possess HIV protease inhibitory activity and are
  • Such cyclic HIV protease inhibitors are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral replication and/or HIV protease, for example in a pharmaceutical research program.
  • cyclic HIV protease inhibitors may be used as a control or reference compound in such assays and as a quality control standard.
  • Such cyclic HIV protease inhibitors may be provided in a commercial kit or container for use as such standard or reference
  • cyclic HIV protease inhibitors exhibit specificity for HIV protease, they may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV protease. Thus, inhibition of the protease activity in an assay by such a cyclic HIV protease inhibitor would be indicative of the presence of HIV protease and HIV virus.
  • Said process comprises one or more of four chemical steps described futher below.
  • the process of the present invention preferably comprises steps (l), (2) and (3) as described above and described further described below.
  • R 22 and R 23 are as defined above.
  • a polar protic solvent is used for this step when the imine reducing agent is sodium cyanoborohydride.
  • Suitable polar protic solvents for this step include: methanol, ethanol, isopropanol, 2-fluoroethanol,
  • 2,2,2-trifluoroethanol ethylene glycol, 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl
  • the preferred solvent is methanol.
  • a nonpolar aprotic solvent is used for this step when the imine reducing agent is sodium
  • Suitable nonpolar aprotic solvents include: toluene, tetrahydrofuran, benzene, dimethoxyethane, acetonitrile, dimethoxymethane, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl methyl ether, cyclohexane, pentane, hexane, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m- , o-, or p-xylene, octane, indane, nonane, or naphthalene.
  • the preferred solvent is toluene, tetrahydro
  • An aprotic solvent is used for this step when the imine reducing agent is pyridine «borane complex.
  • Suitable aprotic solvents include: benzene,
  • cyclohexane pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m- , o-, or p- xylene, octane, indane, nonane, naphthalene,
  • dimethylformamide DMF
  • dimethylacetamide DMAC
  • 1,3- dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMPU
  • 1,3-dimethyl-2-imidazolidinone DAI
  • NMP N-methylpyrrolidinone
  • formamide N- methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N- dimethylpropionamide, tetramethylurea
  • NMP N-methylpyrrolidinone
  • the preferred molar equivalents of the aldehyde is about 2.0 to 2.1.
  • Suitable acids for this step include mineral acids and organic carboxylic or sulfonic acids, such as, by way of example and without limitation, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, acetic acid, formic acid, propionic acid, and citric acid.
  • the preferred acid is an organic carboxylic acid.
  • the most preferred acid is acetic acid.
  • the preferred molar equivalents of acid is about 2.0 to 4.0.
  • Suitable imine reducing agents include formic acid, borohydrides, aluminum hydrides and transition metals.
  • Examples of such imine reducing agents include, by way of example and without limitation: lithium aluminum hydride, diisobutyl aluminum hydride, iron
  • the preferred imine reducing agent is a borohydride or pyridine•borane complex.
  • the preferred borohydride is sodium triacetoxyborohydride.
  • the preferred molar equivalents of imine reducing agent is about 3.0 - 3.5 for sodium cyanoborohydride and sodium triacetoxyborohydride, about 4.5 - 5.5 for sodium borohydride with acetic acid, and about 2.0 - 3.0 for pyridine•borane comlex.
  • a "hindered amine base” is intended to include any of a number of nitrogen containing bases wherein the nitrogen in surrounded by sterically
  • hindered amine bases useful for the present invention include, by way of example and without limitation, aromatic and aliphatic amines, alkyl substituted pyridines, 1,8-diazabicyclo [2.2.2] octane (DABCO), pyridine, 4-pyrrolidinopyridine,
  • the product may be isolated by methods common to the skilled artisan.
  • the preferred method of isolation is extraction of the product into an organic solvent.
  • Step (2) Cyclic urea formation.
  • a suitable aprotic solvent for this step includes: benzene, cyclohexane, pentane, hexane, toluene,
  • cycloheptane methylcyclohexane, heptane, ethylbenzene, m- , o-, or p-xylene, octane, indane, nonane,
  • bromodichloromethane dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene,
  • cyclizing agent is meant a reagent or
  • Suitable cyclizing reagents include but are not limited to: phenyl
  • a preferred cyclizing agent is phosgene or triphosgene.
  • preferred molar equivalents of cyclizing agent is about 1.0 - 2.5 for phosgene and about 0.4 - 0.6 for
  • the preferred hindered amine base is
  • the preferred molar equivalents of hindered amine base is about 2.0 - 4.0.
  • step (3) is necessary since a compound of formula (III), as described herein above, may not be in final form until step (3) is carried out.
  • further deprotection or conversion chemical steps are performed by methods known by one of skill in the art in order to convert the protected diol and the substituents R 4 , R 7 , R 22 and R 23 into their final form and thus prepare a compound of formula (IV) in its final and biologically active form.
  • deprotection and/or conversion chemical steps might also be needed for groups such as, by way of example and without limitation, carboxyls, carbonyls, hydroxyls, and sulfhydryls.
  • a compound of formula (III) is contacted with a reagent or condition or a
  • this step may involve combination of reagents and/or conditions that will effect the removal of functional group protecting groups or the conversion of a first functional group to a second functional group. As such, this step may
  • conversion chemical step refers to any chemical reaction(s), condition(s) or combination (s) thereof where a first functional group is converted to another functional group such as, by way of example and without limitation, the conversion of an ester to an alcohol, the conversion of a nitro to an amine, or the conversion of an amine to a carbamate or an amide.
  • R 20 and R 21 from the cyclic urea of formula (III) to form a compound of formula (IV).
  • a compound of formula (III) in an acid stable solvent is contacted with a reagent or condition or combination or reagents or conditions which will effect the removal of the R 20 and R 21 hydroxyl protecting groups to form a compound of formula (IV).
  • a suitable acid stable solvent for the removal of groups R 20 and R 21 includes: dimethoxymethane,
  • chlorobenzene or fluorobenzene.
  • hydroxyl protecting group refers to any group known in the art of organic synthesis for the protection of hydroxyl groups.
  • hydroxy protecting group reagent refers to any reagent known in the art of organic synthesis for the protection of hydroxy groups which may be reacted with an hydroxy to provide an hydroxy group protected with an hydroxy protecting group.
  • protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1991), the disclosure of which is hereby incorporated by reference.
  • the hydroxy protecting groups are base- stable and can include, but are not limited to acyl types, aromatic carbamate types, ether types and alkyl types. Exemplary are methyl, methoxymethyl (MOM), methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl (SEM), tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl,
  • Suitable hydroxyl protecting groups may also include the following protecting groups as ethers:
  • triphenylmethyl tetrahydrofuranyl, methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 2- trimethylsilylethoxymethyl, t-butoxymethyl,
  • p-methoxyphenyldiphenylmethyl may include: (a) 1-4M HCl in anhydrous or aqueous methanol, ethanol,
  • Conditions to remove benzyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-methoxybenzyl, o- nitrobenzyl, p-nitrobenzyl are: hydrogenolysis in the presence of 1-17% palladium on carbon, or palladium black.
  • Conditions to remove o-nitrobenzyl group include irradiation of the compound at 320 nm wavelength for 5- 60 minutes.
  • Conditions to remove 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl, triisopropylsilyl, t- butyldiphenylsilyl may include: treatment of the compound with tetrabutylammonium fluoride; or hydrogen flouride pyridine complex in THF, DMF or
  • Conditions to remove allyl may include:
  • the compounds of formula (III) of the present invention may contain a cyclic acetal hydroxyl
  • cyclic acetal protecting group includes any protecting group known in the art of organic synthesis for the protection of 1,2 -diol group through formation of a cyclic acetal or cyclic ketal group.
  • protecting groups include, but are not limited to, those listed in Greene and Wuts, "Protective Groups in Organic
  • protecting groups are methylene acetal, ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cycloheptylidene ketal, cyclopentylidene ketal,
  • substituted or unsubstituted carbocyclic diethers such as oxydimethylene-1,3-diyl
  • dithioethers such as oxydimethylene-1,3-diyl
  • mixed ethers such as enol ethers or ketones.
  • the preferred hydroxyl protecting group is
  • acetonide or oxydimethylene-1,3-diyl When it is acetonide, the preferred conditions for removal are treatment of a compound of formula (III) in toluene or chlorobenzene with 2 - 10 molar equivalents of a suitable acid in the presence of 2 - 50 molar
  • a suitable acid includes, by way of example and without limitation, methanesulfonic acid,
  • benzenesulfonic acid hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and toluenesulfonic .
  • the preferred acid is methanesulfonic acid.
  • the preferred molar equivalents is 2.0 - 4.0.
  • the preferred alcohol is methanol.
  • the preferred molar equivalents of alcohol is 10 - 20.
  • the present invention may be further exemplified by
  • the following abbreviations may be used herein and are defined as follows.
  • the abbreviation “Bn” means benzyl.
  • the abbreviation “BOC” means t-butyl carbamate.
  • the abbreviation “CBZ” means benzyl carbamate.
  • asymmetrically substituted carbon atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral,
  • amine protecting group refers to any group known in the art of organic synthesis for the protection of amine groups.
  • amine protecting group reagent refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group.
  • amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference.
  • Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl,
  • aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1- methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc);
  • aliphatic carbamate types such as tert- butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl;
  • cyclic alkyl carbamate types such as
  • cyclopentyloxycarbonyl and adamantyloxycarbonyl 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and
  • Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10- dioxo-10,10,10,10-tetrahydrothio- xanthyl)]methyloxycarbonyl; 2- trimethylsilylethyloxycarbonyl; 2 - phenylethyloxycarbonyl; 1,1-dimethyl-2,2- dibromoethyloxycarbonyl; 1-methyl-1-(4- biphenylyl) ethyloxycarbonyl; benzyloxycarbonyl; p- nitrobenzyloxycarbonyl; 2-(p- toluenesulfonyl) ethyloxycarbonyl; m-chloro-p- acyloxybenzyloxycarbonyl; 5- benzyisoxazolylmethyloxycarbonyl; p- (dihydroxyboryl) benzyloxycarbonyl; m- nitrophen
  • carboxyl protecting group refers to any group known in the art of organic synthesis for the protection of carboxyl groups. Such carboxyl protecting groups include those listed in
  • carboxyl protecting groups include, but are not limited to, the following: 1) substituted methyl ester type such as methoxymethyl, tetrahydropyranyl, benzyloxymethyl, N- phthalimidomethyl; 2) 2 -substituted ethyl ester type such as 2,2,2-trichloroethyl, 2-methylthioethyl, t- butylethyl, cinnamylethyl, benzylethyl, 2-(2'- pyridyl) ethyl; 3) substituted benzyl ester type such as triphenylmethyl, 9 -anthrylmethyl, p-nitrobenzyl, 4- picolyl, 2,4,6-trimethylbenzyl; 4) silyl
  • phenyldimethylsilyl phenyldimethylsilyl
  • miscellaneous type such as oxazole, orthoester
  • amides type such as N,N- dimethyl, piperidinyl, pyrrolindinyl
  • hydrazide type such as alkylated hydrazides.
  • each of the two R 11 substituents on C is independently selected from the defined list of possible R 11 .
  • substituent may be bonded to any atom on the ring.
  • substituent may be bonded via any atom in such substituent.
  • substituent is piperazinyl
  • piperazinyl, piperidinyl, tetrazolyl may be bonded to the rest of the compound of a given formula via any atom in such piperazinyl, piperidinyl,
  • stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl
  • bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.
  • alkenyl is intended to include
  • hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain such as ethenyl, propenyl, and the like
  • alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Such groups may alternatively and equivalently be denoted as “alkylene”, “alkenylene”, “phenylene”, and the like, respectively.
  • Alkylcarbonyl is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location.
  • Alkylcarbonylamino is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location.
  • Alkylcarbonyloxy is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl; the term
  • arylalkyl represents an aryl group attached through an alkyl bridge.
  • C 7 -C 10 arylalkyl is intended to refer to an aryl group attached through a C 1 -C 4 alkyl bridge to the residue of the indicated compound
  • (C 1 -C 3 alkyl) aryl is intended to refer to a C 1 -C 3 alkyl group which is attached through an aryl ring to the residue of the indicated compound
  • aryl (C 1 -C 3 alkyl) is intended to refer to an aryl group attached through a C 1 -C 3 alkyl group to the residue of the indicated compound.
  • carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7 - to 14 -membered bicyclic or tricyclic or an up to 26 -membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl,
  • cyclopentyl cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • heterocycle is intended to mean a stable 5- to 7- membered monocyclic or
  • bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may
  • heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting
  • heterocycles include, but are not limited to, 1H-indazole, 2- pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H- indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
  • phenoxathiinyl phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • amino acid as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur
  • Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids,
  • amino acid residue means that portion of an amino acid (as defined herein) that is present in a peptide.
  • peptide as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond.
  • peptide also includes compounds containing both peptide and non-peptide components, such as
  • peptide bond means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines;
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic,
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally,
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic
  • the diamine (IA) (5.0 g, 14.7 mmol) was dissolved in methanol (100 mL) and stirred under nitrogen. 3- nitrobenzaldehyde (4.88 g, 32.3 mmol) was added and the resulting solution stirred for 2 hours. Glacial acetic acid (1.68 mL, 29.4 mmol) was added followed by sodium cyanoborohydride (2.77 g, 44.1 mmol) in portions. The mixture was stirred overnight and then partioned between methylene chloride and sodium bicarbonate solution. The aqueous phase was extracted twice more with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and
  • the bis p-TsOH salt of the diamine (IA) (6.03 g, 8.81 mmol) was partitioned between toluene (40 mL) and a IN NaOH solution.
  • the toluene solution was washed with IN NaOH, water and brine then dried over Na 2 SO 4 and filtered directly into the reaction flask rinsing with more toluene (20 mL).
  • 3-nitrobenzaldehyde (2.94 g,
  • the bis p-TsOH salt of the diamine (IA) (485 g, 0.69 mol) was suspended in toluene (4 L) and stirred under nitrogen while diisopropyl ethylamine (200 g, 1.65 mol) and 3-nitrobenzaldehyde (234 g, 1.53 mol) were added. The mixture was heated at reflux for 45 minutes and then cooled to 5° C. Glacial acetic acid (100 g, 1.67 mol) was added followed by pyridine-borane complex (220 mL, 1.76 mol). The resulting solution was stirred at room temperature for 2 hours, 60° C for 2 hours and then 90° C for 30 minutes.
  • the bis benzylamine (IIA) 250 g, 0.39 mol was combined with diisopropyl ethylamine (130 g, 1.0 mol) in chlorobenzene (4.1 L) under nitrogen and the mixture heated to 125° C.
  • the bis-nitrobenzyl cyclic urea (IVA) (100.0 g, 0.166 moles), isopropanol (1000 mL), water (150 mL), methanesulfonic acid (21.6 mL, 0.333 moles) and Pd/C (10% wt, 7.1 g) were placed in a stirred round bottom flask. After three purges with hydrogen, the flask was heated to 40 °C under a flow of hydrogen. After
  • Example 2 The procedure described in Example 2 was used to convert the diamino acetonide (IA) into the bis
  • Example 5 The cyclization portion of the procedure described in Example 5 was used to convert the bis benzylamine (IIC) into the cyclic urea (IIIC) in 66% yield after chromatography on silica with methylene chloride. An analytical sample was recrystallized from hexane, mp 138-140° C.

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Abstract

L'invention porte sur des urées (IV) cycliques disubstituées préparées par alkylation réductrice de (I) par des aldéhydes R22-CHO ou R23-CHO en présence d'un agent réducteur qui donne (II) (première étape), suivie d'une cyclocarbonylation de (II) qui donne (III) (deuxième étape) et d'une déprotection de (III) qui donne le diol (IV) (troisième étape), conformément au schéma. Lesdits urées (IV) cycliques s'avèrent d'utiles inhibiteurs des protéases du VIH.
PCT/US1996/008556 1995-06-06 1996-06-04 Procede de preparation d'urees cycliques n,n'-disubstituees WO1996039393A1 (fr)

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EP96917066A EP0830349B1 (fr) 1995-06-06 1996-06-04 Procede de preparation d'urees cycliques n,n'-disubstituees
AT96917066T ATE190974T1 (de) 1995-06-06 1996-06-04 Verfahren zur herstellung von n,n'- disubstituierten cyclischen harnstoffen
AU59752/96A AU700805B2 (en) 1995-06-06 1996-06-04 Method for preparing N, N'-disubstitued cyclic ureas
DK96917066T DK0830349T3 (da) 1995-06-06 1996-06-04 fremgangsmåde til fremstilling af N,N' -di-substituerede cycliske urinstoffer
DE69607344T DE69607344T2 (de) 1995-06-06 1996-06-04 Verfahren zur herstellung von n,n'-disubstituierten cyclischen harnstoffen
MX9709125A MX9709125A (es) 1995-06-06 1996-06-04 Metodo para preparar ureas ciclicas n,n'-disustituidas.
NZ309557A NZ309557A (en) 1995-06-06 1996-06-04 Method for preparing N,N'-disubstituted cyclic ureas
JP9501114A JPH11506765A (ja) 1995-06-06 1996-06-04 Ｎ，ｎ´−ジ置換環状尿素の調製方法
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US5466797A (en) * 1994-06-30 1995-11-14 The Du Pont Merck Pharmaceutical Company Intermediates for the preparation of cyclic urea
US5532357A (en) * 1995-06-07 1996-07-02 The Dupont Merck Pharmaceutical Company Method for preparing N-monosubstituted and N,N'-disubstituted unsymmetrical cyclic ureas
US6054597A (en) * 1995-11-14 2000-04-25 Dupont Pharmaceuticals Processes and intermediates for the preparation of cyclic urea HIV protease inhibitors
AU6870098A (en) * 1997-03-31 1998-10-22 Du Pont Merck Pharmaceutical Company, The Indazoles of cyclic ureas useful as hiv protease inhibitors
US6218534B1 (en) 1997-10-06 2001-04-17 Dupont Pharmaceuticals Company Preparation of asymmetric cyclic ureas through a monoacylated diamine intermediate
US6313110B1 (en) * 1999-06-02 2001-11-06 Dupont Pharmaceuticals Company Substituted 2H-1,3-diazapin-2-one useful as an HIV protease inhibitor
WO2001092652A1 (fr) * 2000-05-30 2001-12-06 Red Valve Co., Inc. Procede et dispositif permettant d'empecher la stagnation dans les reservoirs de liquide
FR2810039B1 (fr) * 2000-06-13 2007-05-25 Centre Nat Rech Scient Composes urees cycliques et leur procede de preparation
EP2228369A1 (fr) 2003-12-23 2010-09-15 Astex Therapeutics Ltd. Derives de pyrazole comme modulateurs de proteine kinase
JP2008546751A (ja) * 2005-06-22 2008-12-25 アステックス・セラピューティクス・リミテッド 医薬組成物
JP5345842B2 (ja) 2005-06-23 2013-11-20 アステックス・セラピューティクス・リミテッド プロテインキナーゼモジュレーターとしてのピラゾール誘導体を含む医薬組み合わせ
US20080033167A1 (en) * 2005-12-29 2008-02-07 Gilles Guichard Compositions and methods for synthesizing heterocyclic therapeutic compounds
GB0704932D0 (en) 2007-03-14 2007-04-25 Astex Therapeutics Ltd Pharmaceutical compounds
KR101663255B1 (ko) * 2015-11-30 2016-10-10 주식회사 삼양사 안정성이 향상된 농축 무수당 알코올 제조용 조성물 및 무수당 알코올의 농축 방법
KR101663264B1 (ko) * 2015-11-30 2016-10-10 주식회사 삼양사 저장 안정성이 향상된 무수당 알코올 조성물 및 무수당 알코올의 저장 방법

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ATE190974T1 (de) 2000-04-15
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DE69607344D1 (de) 2000-04-27
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